Ultrasound assisted synthesis and spectral correlations of some bio-active E-imines

doi:10.21203/rs.3.rs-4438867/v1

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Ultrasound assisted synthesis and spectral correlations of some bio-active E-imines

https://doi.org/10.21203/rs.3.rs-4438867/v1

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published 14 Aug, 2024

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Some aryl E-imines were synthesized by nano fly-ash H₃PO₄ catalyzed condensation of various aryl anilines and benzaldehydes under ultrasound irradiated greener solvent medium. In this condensation the obtained yield was more than 75%. These E-imines were characterized by their physico-chemical data, micro analysis and spectroscopic data. The characteristic spectral frequencies were employed for spectral QSAR study. The spectral QSAR study was performed with single and multi-regression analysis using Hammett σ, σ, σ_I, σ_R F R and Swain-Lupton’s constants. From the outcome of the regression, the effect of substituents on the spectral frequencies were predicted. The molecular docking study of these imines were performed by the assessment of protein -ligand interaction study with a characteristic protein. The antimicrobial activities of these imines were studied using Bauer-Kirby disc diffusion technique with various bacterial and fungal microbes. The in-vitro antimalarial activity of these imines was measure using P. Falciparum Thai protein-microbes.

E-imines

nano fly-ash H3PO4 catalyst

Ultrasonication

QSAR

Bio-activities

The E-imine or azomethine or Schiff’s bases are a nitrogenous substrate possess -N = CH- moieties and both terminals are linked with aliphatic or aryl groups. They are the precursor for organic building scaffolds and they play an important role in medicinal and pharmaceutical industries due to presence of vast significant biological activities [1]. These Schiff’s bases were synthesized by conventional heating or the greener synthetic methods such as microwave irradiation or ultrasound irradiation or Grinding techniques [2–5]. Numerous catalysts were employed for the synthesis of the above methods such as Lewis-acid and bases [6, 7], acetates [7], acetic acid [8], silica [9], fly-ash based catalysts [10, 11], metal oxides [12], buffer solutions [13], MCM [14], and nano catalysts [15, 16]. Huge numbers of E-imines were synthesized using the above synthetic methods such as, Trifluoromethyl imine [10], naphthyl imines [17], benzylidene benzenes [18], heterocyclic imines [19], diamines [20]. Spectral data are very informative for the prediction of their ground state equilibration and configurations of organic substrates such as E or Z type [21]. Various Hammett substituent constants, F and R parameters were utilized for the study of effects of substituents on the spectral frequencies of imines. [10, 18]. Thirunarayanan et al have reported the solvent-free synthesis spectral correlations and biological activities of some trifluoromethyl imines [10, 22, 23]. Suresh et al., studied the greener synthesis and spectral QSAR and antimicrobial activities of some 4-methoxy benzylidene benzenes [18]. Synthesis and spectral correlation study of some diimines was reported by Thirunarayanan [20]. Mayavel et. al., studied the solvent-free synthesis, XRD, spectral and antibacterial activities of some (E)-N-(4-nitrobenzylidene)-1-benzylpiperidin-4-amines [24, 25]. Sakthinathan et. al. reported the synthesis, effect of substituents on spectral frequencies and antimicrobial activities of some substituted benzylidene 2-chloro-4-methyl anilines [26]. Dineshkumar et al., studied the synthesis, crystal, spectral and antimicrobial activities of some(E)-N-(substituted arylidene)-3-(trifluoromethyl)anilines [27]. Molecular docking is the one of the tools for finding the polar interactions of various proteins and the ligand of imines. The molecular computational outcome of these study shows the rate of actions of drugs in metabolism. Various proteins utilized for studying the ligand interactions such as (5GWK) [28, 29]. The -N = CH- moiety and presence of polar substituents are the origin for the biological activities of E-imines. Schiff’s bases possess vast number of bio-activities such as antimicrobial [24, 25], anti-viral, anti-HIV [30], anti-inflammatory [31], anti-tumor [32], anti-fertility [33], anti-plasmodial [34], anti-leishmanial [35], cardio vascular [36], anti-cancer [37] and anti-malarial [38–42]. Guillon et al reported the synthesis, design and antimalarial potency of some novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives[38]..Ressurreição et. al.[39] has studied the structural optimization and dual stage antimalarial activities of some quinoline 4(1H) imine derivatives. Kumar et al. investigated the drug-resistant malarial activities of some imine heterocyclic scaffolds. Jarrahpour and his co-workers [40] studied the in-vitro antimalarial activities of some spiro β-lactam-isatin hybrids. The molecular fashion and β-Hematin interactions based antimalarial activity of some hyrodxypyridinone imines were studied by Fayyazi et al., [41]. The QSAR study of antimalarial activities of some quinolon-4(1H)-imines were reported by Duarte et al., [42]. From the literature review, there is no report availed for the ultrasonicated synthesis spectral correlation, molecular docking, antimicrobial and anti-malarial activities of some series of 1-benzyl piperidine amine, 4-morpholino amine and 2-amino-3,4-dibromo benzaldehyde-based imines. Hence the authors taken efforts to synthesis and studied the structure, spectral correlation and bio properties of above imines.

Materials and Methods

Sigma Aldrich Chemical company manufactured chemicals used in this research work. Suntex melting point apparatus was used for measuring melting point of all synthesized compounds and are uncorrected. The FT-IR spectra of all imines were recorded in Avatar-300 Thermo Nicolet Fourier Transform infrared spectrophotometer (4000-400cm^− 1) using potassium bromide disc. The ¹H NMR and ¹³C NMR spectra of all synthesized imines were recorded in BRUKER AVANCE III 500 MHz NMR spectrophotometer at 400 MHz for ¹H NMR spectra and 100.61 MHz for ¹³C NMR spectra. Chloroform-D₆ used as solvent with TMS as standard. The LCMS mass spectra of all compounds were recorded in the Water Micro TOF Qii spectrometer in EI mode. The CHN analysis results was obtained from VARIOMICRO V2.2.0 elemental analyzer.

General procedure for the Synthesis of E-imines (1–28)

An equal molar quantities of aryl amines (1 mmol) substituted benzaldehydes (1 mmol) and 0.3 mg of nano fly-ash H₃PO₄ catalyst [43] and 20 mL of ethanol were ultrasonicated in ultrasonication bath at 40 Hz, in room temperature for 6–13 m (Scheme 1) (Citizen Ultra Sonicator, 40 Hz, 120W, 240V, AC). The progress of the reaction was monitored using TLC. After completion of the reaction, the product was separated by simple filtration and evaporation of ethanol gave the crude product. The catalyst was washed with ethyl acetate and reused for further reactions. The crude was recrystallized with ethanol afforded the corresponding E-imines. The yield, time and physical constants of the synthesized imines are tabulated in Table 1.

Table 1

The physiochemical constants, time and yields of the synthesized E-imines

Entry	Ar	Ar′	M.F.	M.W	Yield (%)	Time (m)	M.p. (˚C)
1	4-Phenylmorpholine	Phenyl	C₁₇H₁₈N₂O	266	85	7	178–180
2	4-Phenylmorpholine	3-Bromophenyl	C₁₇H₁₇BrN₂O	345	79	8	101–103
3	4-Phenylmorpholine	4-Bromophenyl	C₁₇H₁₇BrN₂O	345	78	8	188–191
4	4-Phenylmorpholine	3-Chlorophenyl	C₁₇H₁₇ClN₂O	301	81	8	110–112
5	4-Phenylmorpholine	4-Chlorophenyl	C₁₇H₁₇ClN₂O	301	83	9	150–152
6	4-Phenylmorpholine	4-Dimethylaminophenyl	C₁₉H₂₃N₃O	309	86	7	230–232
7	4-Phenylmorpholine	4-Florophenyl	C₁₇H₁₇FN₂O	284	80	10	140–142
8	4-Phenylmorpholine	3-Methoxyphenyl	C₁₈H₂₀N₂O₂	296	87	8	86–88
9	4-Phenylmorpholine	2-Methylphenyl	C₁₈H₂₀N₂O	280	84	9	80–82
10	4-Phenylmorpholine	4-Methylphenyl	C₁₈H₂₀N₂O	280	83	9	158–160
11	4-Phenylmorpholine	4-Nitrophenyl	C₁₇H₁₇N₃O₃	311	75	12	199–201
12	Phenyl	2-Amino-4,6-dibromophenyl	C₁₃H₁₀Br₂N₂	354	78	13	136-137134-136[44]
13	4-Bromophenyl	2-Amino-4,6-dibromophenyl	C₁₃H₉Br₃N₂	432	76	10	197-198196-198[44]
14	4-Chlorophenyl	2-Amino-4,6-dibromophenyl	C₁₃H₉Br₂ClN₂	388	77	12	180-181182-184[44]
15	4-Florophenyl	2-Amino-4,6-dibromophenyl	C₁₃H₉Br₂FN₂	372	77	11	166-167164-166[44]
16	4-Methoxyphenyl	2-Amino-4,6-dibromophenyl	C₁₄H₁₂Br₂N₂O	384	83	12	108-109106-108[44]
17	4-Methylphenyl	2-Amino-4,6-dibromophenyl	C₁₄H₁₂Br₂N₂	368	82	11	113-115114-116[44]
18	1-Benzyl-4-piperidinyl	Phenyl	C₁₉H₂₂N₂	278	81	8	66–67(64–65)[25]
19	1-Benzyl-4-piperidinyl	3-Bromophenyl	C₁₉H₂₁BrN₂	357	79	9	60–61(59–60) [25]
20	1-Benzyl-4-piperidinyl	3-Chlorophenyl	C₁₉H₂₁ClN₂	312	78	11	55–56(53–54) [25]
21	1-Benzyl-4-piperidinyl	4-Chlorophenyl	C₁₉H₂₁ClN₂	312	79	10	103–104(102–103) [25]
22	1-Benzyl-4-piperidinyl	4-Dimethylaminophenyl	C₂₁H₂₇N₂	321	86	11	58–59(57–58) [25]
23	1-Benzyl-4-piperidinyl	4-Fluorophenyl	C₁₉H₂₁FN₂	296	80	11	94–95(92–93) [25]
24	1-Benzyl-4-piperidinyl	3-Methoxyphenyl	C₂₀H₂₄N₂O	308	86	9	64–65(63–64) [25]
25	1-Benzyl-4-piperidinyl	4-Methoxyphenyl	C₂₀H₂₄N₂O	308	84	7	51–52(49–50) [25]
26	1-Benzyl-4-piperidinyl	4-Methylphenyl	C₂₀H₂₄N₂	292	83	9	54–55(51–52) [25]
27	1-Benzyl-4-piperidinyl	3-Nitrophenyl	C₁₉H₂₁N₃O₂	323	76	11	62–63(60–61) [25]
28	1-Benzyl-4-piperidinyl	4-Nitrophenyl	C₁₉H₂₁N₃O₂	323	77	12	84–85(82–83) [25]

The spectroscopic data and elemental analysis of the E-imines (1–11) as summarized as follows.

( E )-N-Benzylidene-4-morpholinianilie (1): FT- IR (KBr, cm^− 1); ν = 1623.44(C = N), 1232.03 (C-N), 2961.00(CH), 1448.91 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.498 (s, 1H, CH), 3.185 (s, 4H, N-(CH₂)₂), 3.879 (s, 4H, O-(CH₂)₂, 6.939–7.888(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 157.91 (C = N), 49.50(N-CH₂), 66.92(O-CH₂), 116.18-149.95 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 266 [M¹⁺] 190, 189, 186, 180, 176, 104, 91, 78, 77, 27.

( E )-N-(3-Bromobenzylidene)-4-morpholinoaniline (2): FT- IR (KBr, cm^− 1); ν = 1625.10(C = N), 1229.86 (C-N), 2964.65(CH), 1445.35 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.437 (s, 1H, CH), 3.197 (s, 4H, N-(CH₂)₂), 3.880 (s, 4H, O-(CH₂)₂, 6.661–8.078(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 155.68 (C = N), 49.31(N-CH₂), 66.09(O-CH₂), 116.06-150.28 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 345[M¹⁺], 347[M²⁺], 265,189,182,176, 168, 162, 156, 91, 79, 77, 27.

( E )-N-(4-Bromobenzylidene)-4-morpholinoaniline (3): FT- IR (KBr, cm^− 1); ν = 1620.93(C = N), 1232.12 (C-N), 2958.23(CH), 1487.12 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.446(s, 1H, CH), 3.192 (s, 4H, N-(CH₂)₂), 3.880 (s, 4H, O-(CH₂)₂, 6.934–7.764(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 156.18 (C = N), 49.36(N-CH₂), 66.89(O-CH₂), 116.10-150.16 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 345[M¹⁺], 347[M²⁺], 265, 189, 182, 176, 168, 162, 156, 91, 79, 77, 27.

( E )-N-(3-Chlorobenzylidene)-4-morpholinoaniline (4): FT- IR (KBr, cm^− 1); ν = 1619.68(C = N), 1245.23 (C-N), 2954.19 (CH), 1467.14 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.447 (s, 1H, CH), 3.194 (s, 4H, N-(CH₂)₂), 3.878 (s, 4H, O-(CH₂)₂, 6.936–7.918(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 155.80 (C = N), 49.55(N-CH₂), 66.42(O-CH₂), 116.11-150.21 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 300[M⁺], 302[M²⁺], 265, 214, 189, 176, 162, 138, 124, 111, 86, 77, 35, 27.

( E )-N-(4-Chlorobenzylidene)-4-morpholinoaniline (5): FT- IR (KBr, cm^− 1); ν = 1620.85(C = N), 1265.17 (C-N), 2962.47 (CH), 1465.195 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.460 (s, 1H, CH), 3.192 (s, 4H, N-(CH₂)₂), 3.880 (s, 4H, O-(CH₂)₂, 6.935–7.833(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 156.12 (C = N), 49.38(N-CH₂), 66.90(O-CH₂), 116.11-150.14 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 300[M⁺], 302 [M²⁺], 265, 214, 189, 176, 162, 138, 124, 111, 104, 86, 77, 35, 27.

( E )-N-(4-Dimethylaminobenzylidene)-4-morpholinoaniline (6): FT- IR (KBr, cm^− 1); ν = 1607.92(C = N), 1238.28 (C-N), 2954.29(CH), 1438.18 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.351 (s, 1H, CH), 3.167 (s, 4H, N-(CH₂)₂), 3.879 (s, 4H, O-(CH₂)₂, 6.723–7.769(m, 9H, Ar-H), 3.052(s, 6H, (CH₃)₂). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 157.60 (C = N), 49.55(N-CH₂), 66.93(O-CH₂), 19.43 (CH₃), 116.25–149.90 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 309[M⁺], 294, 279, 265, 223, 189, 179, 176, 162, 147, 133, 120, 103, 86, 76, 44, 30, 15 .

( E )-N-(4-Fluorobenzylidene)-4-morpholinoaniline (7): FT- IR (KBr, cm^− 1); ν = 1622.51(C = N), 1232.39 (C-N), 2970.13(CH), 1447.44 (C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.457 (s, 1H, CH), 3.123 (s, 4H, N-(CH₂)₂), 3.891 (s, 4H, O-(CH₂)₂, 6.944–7.766(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 156.27 (C = N), 49.45(N-CH₂), 66.91(O-CH₂), 115.77–150.00 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 284[M⁺], 286[M²⁺], 265, 198, 179, 176, 162, 122, 108, 103, 95, 91, 89, 77, 27, 19.

( E )-N-(3-Methoxybenzylidene)-4-morpholinoaniline (8): FT- IR (KBr, cm^− 1); ν = 1621.74(C = N), 1288.79 (C-N), 2958.12(CH), 1467.29(C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.467 (s, 1H, CH), 3.889 (s, 4H, N-(CH₂)₂), 3.889 (s, 4H, O-(CH₂)₂, 6.938–7.509(m, 9H, Ar-H), 3.188(s, 3H, OCH₃). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 157.77 (C = N), 49.47(N-CH₂), 66.92(O-CH₂), 55.52 (OCH₃), 111.63-149.98 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 265[M⁺], 210, 184, 179, 162, 134, 128, 120, 107, 103, 91, 89, 77, 31, 15.

( E )-N-(2-Methylbenzylidene)-4-morpholinoaniline (9): FT- IR (KBr, cm^− 1); ν = 1617.44(C = N), 1247.29 (C-N), 2971.09(CH), 1442.19(C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.446 (s, 1H, CH), 3.184 (s, 4H, N-(CH₂)₂), 3.883 (s, 4H, O-(CH₂)₂, 6.935–7.788(m, 9H, Ar-H), 2.425(s, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 156.66 (C = N), 49.55(N-CH₂), 66.93(O-CH₂), 19.43 (CH₃), 116.25–149.90 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 280 [M¹⁺], 265, 194, 189, 179, 176, 162, 118, 103, 91, 89, 85, 77, 27, 15.

( E )-N-(4-Methylbenzylidene)-4-morpholinoaniline (10): FT- IR (KBr, cm^− 1); ν = 1619.41(C = N), 1246.32 (C-N), 2969.14(CH), 1462.76(C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.457 (s, 1H, CH), 3.180 (s, 4H, N-(CH₂)₂), 3.8789 (s, 4H, O-(CH₂)₂, 6.932–7.785(m, 9H, Ar-H), 2.411(s, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 157.97 (C = N), 49.55(N-CH₂), 66.94(O-CH₂), 29.73 (CH₃), 116.22-149.79 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 280[M+], 265, 194, 189, 179, 176, 162, 118, 103, 91, 89, 85, 77, 27, 15.

( E )-N-(4-Nitrobenzylidene)-4-morpholinoaniline (11): FT- IR (KBr, cm^− 1); ν = 1597.73(C = N), 1288.23(C-N), 2978.25(CH), 1469.24(C-O-C). ¹H NMR (400 MHz, CDCl₃, ppm) δ = 8.598 (s, 1H, CH), 3.226 (s, 4H, N-(CH₂)₂), 3.886 (s, 4H, O-(CH₂)₂, 6.951–8.322(m, 9H, Ar-H). ¹³C NMR (100 MHz, CDCl₃, ppm) δ = 158.93 (C = N), 49.85(N-CH₂), 66.99(O-CH₂), 116.98-149.98 (Ar-C). Anal. C (76.66), H (6.81), N (10.52); Found (%): C (76.61), H (6.77), N (10.50). LCMS (m/z) = 311 [M⁺], 265, 225, 189, 179, 176, 162, 149, 135, 122, 103, 89, 86, 77, 46, 27.

The characteristic spectral frequencies of (E)-3,5-Dibromo-2-((4-substituted phenylimino) methyl) anilines (11–17) are summarized in Table 2.

Table 2 The infrared, NMR and Mass spectral data of (E)-3,5-Dibromo-2-((4-substituted phenylimino) methyl) anilines (11-17).

Entry	Substt.	IR (ν, cm^− 1)		¹H NMR (δ, ppm)			13C NMR (δ, ppm)		Mass(m/z)
Entry	Substt.	NH	C = N	NH	CH	Subtt.	C = N	Subtt.	Mass(m/z)
12	H	3378.64	1616.97	4.185	8.314	---	155.66	---	354[M⁺], 356[M²⁺], 358[M4⁺], 336, 273, 262, 248, 245, 232,196, 194, 117, 104, 91, 79, 77, 24, 16
13	Br	3329.22	1635.59	4.253	8.513	---	155.21	---	433[M⁺], 435[M²⁺], 437[M⁴⁺], 439[M⁶⁺], 414, 351, 335, 275, 262, 259, 248, 245, 232, 182, 169, 155, 79, 77, 16
14	Cl	3361.96	1633.99	4.179	8.511	---	155.21	---	388[M⁺], 390[M²⁺], 392[M4⁺], 394[M6⁺], 360, 307, 291, 272, 256, 245, 232, 196, 182, 138, 125, 111, 79, 77, 35, 16
15	F	3264.03	1613.46	4.901	8.507	---	155.20	---	372[M⁺], 374[M²⁺], 376[M4⁺], 378[M6⁺], 357, 351, 276, 274, 259, 248, 245, 232, 181, 167, 154, 122, 109, 95, 79, 27, 19, 16.
16	OCH₃	3391.30	1637.18	4.085	8.314	3.385	155.66	52.08	414[M⁺], 416[M²⁺], 418[M⁴⁺], 366, 351, 335, 287, 278, 261, 259, 245, 234, 134, 121, 107, 91, 79, 77, 31, 16, 15.
17	CH₃	3448.71	1636.35	4.066	8.523	2.356	155.25	27.05	368[M⁺], 370[M²⁺], 372[M4⁺], 350, 271, 259, 245, 232, 180, 166, 153, 118, 105, 91, 79, 77, 27, 16, 15

Molecular docking analysis

Auto Dock Tools-1.5.7 was employed to run docking interactions on different substituted imine derivatives with breast cancer protein. The Protein Data Bank (PDB) was utilized to acquire the crystal structure of human estrogen receptor (PDB ID: 2IOK) [45–47]. The Protein Data Bank (PDB) delivered the crystal structure of the protein receptor, which was assisted in this work. The ligand structures were constructed in the CDX format by using Chem Draw ultra-version 8.0. Open Babel-2.5.7 was exploited to convert the prepared ligand in CDX format into PDB format. Next, a PDBQT file was arranged, grid box size and center were placed. Kollman charges and polar hydrogen atoms were added to the protein structure of 2IOK. The grid size was position at 80, 90, 80 (x, y, and z) points respectively. This file was pinned and stored in PDBQT format. Ligand binding affinities were noticed as negative Gibbs free energy (ΔG) scores (kcal/mol). The docking pose analysis was detected with Discovery studio, which displays the binding sites, hydrogen-bonding interactions, hydrophobic interactions, and bond distances.

Measurement of Antibacterial activity

The antimicrobial activities of the imines (1–11) were measured using the standard Bauer-Kirby[48] disc diffusion method. There are each three gram positive and gram negative microbes were used for the measurement of the antibacterial activities of the synthesized E-N-(substituted benzylidene)(-4-morpholinanilines(1–11) such as, Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. In each petri-plate about 0.5 mL of the test bacterial sample was spread uniformly over the solidified Mueller-Hinton agar using sterile glass spreader. Then the disc with 5 mm diameter made up of Whatman No. 1 filter paper, impregnated with the solution of the compound were placed on the medium using sterile forceps. The plates were incubated for 24 h at 37°C by keeping the plates upside down to prevent the collection of water droplets over the medium. After 24 h the plates were visually examined and the diameter values of the zone of inhibition were measured. Triplicate results were recorded by repeating the same procedure.

Measurement of Antifungal activity

Antifungal activities of the synthesized E-N-(substituted benzylidene)(4-morpholinanilines (1–11) were measured using three fungal strains such as Aspergillus niger, Mucor species and Trichoderma viride. The PDA medium was prepared and sterilized as above. It was poured (ear bearing heating condition) in the petri-plate, which was already filled with 1 mL of the fungal species. The plate was rotated clockwise and counter clockwise for uniform spreading of the species. The disc was impregnated with the test solution. The test solution was prepared by dissolving 15 mg of the imine in 1 mL of DMSO solvent. The medium was allowed to solidify and kept for 24 h. Then the plates were visually examined and the diameter values of zone of inhibition were measured. Triplicate results were recorded by repeating the same procedure.

Measurement of Antimalarial activity

Procedure: Parasite culture: The P. falciparum Thailand strain Thai and strain K1 used for this cell culture [38–42]. Culture was grown in complete medium consisting RPMI1640 supplemented with 11mM glucose, 27.5 mM medium hydrogen carbonate, 100 UI/ml penicillin, 100 µL/ml streptomycin and 8% heat-inactivated human serum albumin. Parasites was grown at 37°C, in human A + red blood cells (RBCs) at a 2% hematocrit, under 3% CO₂, 6% oxygen and 91% nitrogen atmosphere. The in vitro assays were performed cultures with a 3–6% parasitemia as determined by counting parasites on Giemsa-stained smears.

Inhibition Tests

Increasing concentration of the synthesized imines were dissolved in dimethyl sulfoxide (DMSO) and tested for their inhibitory effect towards the P. falciparum intraerythrocytic development. Parasites were allowed to grow at 37°C for 24h in a candle jar, the 0.5µCi ³H-hypoxanthine was added per well. After an additional 24 h incubation period, plates are freeze thawed and harvested on filters. Dried filters were moistened in scintillation liquid mixture and counted in a 1450 Microbeta counter. The growth inhibition in percent was calculated from the parasite associated radioactivity. Hundred percent ³H-hypoxanthine incorporation was determined from control growth in the absence of the retinoid-like chalcones. Values for the IC₅₀ were determined. Each mean concentration was estimated from three different experiment sets.

Chemistry

In our research laboratory, we attempt to synthesis some imines using green catalyst under ultrasonication technique. As mentioned in the experimental section we synthesized more than 75% yields of three series of imines. Here we observed that, the electron-withdrawing substituents yields are lower than the electron donating substituents. This condensation undergoes well known acid catalyzed nucleophilic addition to carbonyl carbon, followed by elimination of water afforded the E-imines. The probable reaction mechanism of this condensation was illustrated in Scheme 2. The first step is the probation of aldehydic carbonyl oxygen by the hydrogen supplies from the acidic site of the nano fly-ash: H₃PO₄ catalyst, then the carbonyl carbon gets positive charge. Second step is the carbon was attached by the amine nucleophile then the nitrogen gets positive charge. This positive charge was neutralized by loss of proton. Third step is the loss of water through beta elimination produce the imines.

The purities of synthesized imines were analyzed through their physical constants, micro analysis and spectroscopic data. These data are supported the formation of imines. In this condensation the effect of catalyst was studied for the imine (1). As the catalyst was increases from 0.05 to 0.5 mg with the addition of 0.05 mg for each reaction step. Simultaneously, the yield of the product was increases from 38 to 85%. The optimum quantity of the catalyst need for this condensation was found to be 0.35 mg. Beyond this quantity of the catalyst there is no change occurs in the yield. The effect of catalyst on this condensation was illustrated in Fig. 1.

Similarly, the effect of solvent on the synthesis of the imine (1) was studied with some solvents such as acetonitrile, ethanol, methanol, dioxane, dichloromethane and tetrahydrofuran with same condition as mentioned in the experimental section. From this study higher yields are obtained in ethanol medium. The least yield obtained in acetonitrile and dioxane medium. In this study the obtained yields are in the range of 38–85% and it is illustrated in the Table 3.

Table 3. The effect of solvent on the synthesis of imine (1).

Solvent	ACN	DCM	DO	EtOH	MeOH	THF
Yield (%)	38	43	56	85	79	38
ACN: Acetonitrile; DCM: Dichloromethane; DO: Dioxane; EtOH: Ethanol; MeOH: Methanol; THF: Tetrahydrofuran

Spectral correlations

Inferred spectral correlations

In infrared spectral correlations, the assigned C = N vibrations were correlated with various Hammett substituent constants [10, 18, 20, 22–27] and Swain-Lupton’s constants[49] using single and multi-linear regression analysis. In this study the Hammett equation was employed as in Eq. (1).

ν = ρσ + ν₀ …(1)

Where ν₀ is the frequency for the parent number of the series.

The results of the statistical analysis are presented in Table 4. From the Table 4, it is observed that the infrared stretching frequencies (ν_C=N, cm^-1) of aryl (E)-imine compounds except those with 4-NO₂ substituent have shown satisfactory correlation with Hammett substituent constants σ (r = 0.901) and σ⁺ (r = 0.901).

Table 4

Results of statistical analysis of infrared frequencies (νNH and C = N, cm^− 1) of substituted (E)-N benzylidene-4-morpholinoanilines and (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines with Hammett substituent constants (σ, σ⁺, σ_I, σ_R) and F and R parameters
Frequency	Constants	r	I	ρ	s	n	Correlated derivatives
(E)-N benzylidene-4-morpholinoanilines
ν_C=N	σ	0.901	1618.15	–2.525	8.42	10	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-CH₃
	σ⁺	0.903	1617.84	1.671	8.40	10
	σ_I	0.774	1619.52	–5.575	8.35	11	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-CH₃, 4-NO₂
	σ_R	0.832	1616.05	–9.060	8.25	11
	F	0.817	1619.78	–6.551	8.28	11
	R	0.745	1617.54	–1.187	8.47	11
(E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines
νNH₂	σ	0.900	3364.03	-171.94	57.15	5	H, Br, Cl, OCH₃, CH₃
	σ⁺	0.960	3354.94	-68.88	62.22	4	H, Br, Cl, CH₃
	σ_I	0.923	3416.89	-203.23	39.48	6	H, Br, Cl, F, OCH₃, CH₃
	σ_R	0.900	3401.36	174.87	59.13	6	H, Br, Cl, F, OCH₃, CH₃
	F	0.987	3424.36	-194.92	31.72	6	H, Br, Cl, F, OCH₃, CH₃
	R	0.904	3598.27	123.27	61.37	6	H, Br, Cl, F, OCH₃, CH₃
νCN	σ	0.901	1629.01	-8.76	11.82	4	H, F, OCH₃, CH₃
	σ⁺	0.902	1628.34	-5.39	11.74	4	Br, Cl, OCH₃, CH₃
	σ_I	0.807	1629.78	-3.00	11.96	6	H, Br, Cl, F, OCH₃, CH₃
	σ_R	0.901	1630.49	7.02	11.90	4	Br, Cl, F, CH₃
	F	0.825	1631.96	-9.55	11.60	6	H, Br, Cl, F, OCH₃, CH₃
	R	0.906	1629.85	3.17	11.96	4	Br, Cl, F, CH₃

r – Correlation coefficient; I – intercept; r – slope; s – standard deviation; n – number of substituents.

When the substituents that have been given exception are included in regression they reduced the correlation considerably. However infrared stretching frequencies (ν_C=N, cm^-1) of substituted (E)-N benzylidene-4-morpholinoanilines have shown poor correlations (r < 0.900) with the remaining Hammett substituent constants σ_I, σ_R and F and R parameters.

This is attributed to the weak polar, inductive and field effects of the substituents for predicting the reactivity on the stretching frequency through resonance as per the conjugative structure as shown in Fig. 2

All the correlations have shown negative ρ values except σ⁺ constant. This reveals the operation of reverse substituent effect with respect to IR stretching frequencies (νC = N, cm^− 1) of substituted (E)-N benzylidene-4-morpholinoanilines.

Since some of the single regression analysis, have shown poor correlations with a few Hammett substituent constants and F and R parameters [49]. It is decided to go for multi-regression analysis. The multi-regression analysis of the IR stretching frequencies (νC = N, cm^− 1) of aryl (E)-imine compounds with inductive, resonance and Swain-Lupton’s parameters produce satisfactory correlations as shown in equations (2 and 3).

ν_C=N (cm^-1) = 1617.57(±5.190) – 4.639(±0.963) σ_I – 8.279(±3.377)σ_R … (2) (R = 0.927, n = 11, P > 95%)

ν_C=N (cm^-1) = 1619.41(±4.736) – 6.583(±0.385) F – 1.309(±0.961) R … (3)

(R = 0.922, n = 11, P > 95%)

The NH and CN vibrations of (νcm-1) of (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines (11–17) were correlated with Hammett substituent constants [10, 18, 20, 22–27] and Swain-Lupton’s parameters [49]. From the table 3, the Hammett sigma constants, F and R parameters were shown satisfactory correlation coefficients. Among all the correlations, the field effect of the substituents is better for reflecting their substituent effects on the amino stretches. The Hammett sigma constant shows least correlation coefficient. The Hammett sigma and sigma plus constants showed satisfactory correlations except F and OCH₃ substituents. The electronegativity and -I effect of methoxy groups reduced the correlation coefficient and the slope was pulled to negative values. The correlations of resonance parameters show positive ρ values. Remaining Hammett parameters shows negative ρ values. This is due to the resonance and conjugative structures of the imines as shown in Fig. 3.

From the table 3, the correlation of CN frequencies, the Hammett σ, σ⁺, σ_R constants and R parameters were shown satisfactory correlation coefficients. Among all the correlations, the resonance effect of the substituents is better for reflecting their substituent effects on the C = N stretches. The Hammett sigma constant shows satisfactory correlation coefficient with negative rho value except Br and Cl substituents. The Hammett sigma plus constants showed satisfactory correlations along with negative rho value except H and F substituents. The inductive and Field effects are failed in the correlations and shows negative rho values. The resonance components show satisfactory correlation coefficients with positive rho values except H and methoxy substituents. The negative ρ value indicates the operation of reversal substituent effects on the CN stretches. This is due to the resonance-conjugative structures of the imines as shown in Fig. 3.

Some of the single parameter correlations were fails, then the authors studied the multi-regression analysis for finding the effect of substituents on the amino group using σ⁺, σ_R, F, R and Swain-Lupton’s constants [10, 18, 20, 22–27, 49]. The obtained the multilinear regression analysis shows a good correlation as in equations 4–7.

νNH₂ (cm^− 1) = 3421.37(± 32.29) – 196.40(± 101.30)σ_I + 15.26(± 131.33) σ_R …(4)

R = 0.992, P > 95%, n = 6

νNH₂ (cm^− 1) = 3416.76(± 23.49) – 234.40(± 71.85)F − 69.14(± 0.80)R …(5)

R = 0.990, P > 95%, n = 6

νCN (cm^− 1) = 1630.47(± 9.75) + 0.20(± 0.30)σ_I + 7.19(± 41.20) σ_R …(6)

R = 0.912, P > 90%, n = 6

νCN (cm^− 1) = 1631.12(± 6.36) – 14.56(± 28.66)F − 8.78(± 34.36)R …(7)

R = 0.928, P > 90%, n = 6

NMR spectral correlations

¹ H NMR Spectral correlations

The signal of the imine proton of substituted (E)-N benzylidene-4-morpholinoanilines. has been assigned. These chemical shifts were correlated with Hammett substituent constants and F and R parameters using single and multi-regression analysis [10, 18, 20, 22–27, 49].

While seeking Hammett correlation involving the chemical shift values, the form of the Hammett equation employed is as shown in Eq. (8).

δ = ρσ + δ₀ … (8)

Where δ₀ is the ¹H NMR chemical shift of the corresponding parent compound.

The results of statistical analysis are shown in Table 5. From Table 5, it is observed that the ¹H NMR chemical shifts (δ_CH=N, ppm) of substituted (E)-N benzylidene-4-morpholinoanilines compounds have shown satisfactory correlation with Hammett substituent constant σ_R (r = 0.904) and R (r = 0.903) parameter except 2-CH₃ substituent. The remaining Hammett substituent constants σ, σ⁺, σ_I and F parameter were failing in correlation. When the substituents that have been given exception are included in regression they reduced the correlation considerably. All the correlation gave positive ρ values except σ_I and F. This shows that the normal substituent effects operate in all system. The reason for the poor correlation is the incapability of the substituent on the substituted (E)-N benzylidene-4-morpholinoanilines chemical shifts and is associated with the resonance conjugated structure as shown in Fig. 2.

Table 5. Results of statistical analysis of 1H NMR chemical shifts (σCH=N, and NH ppm) of substituted (E)-N benzylidene-4-morpholinoanilines and (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines with Hammett substituent constants (σ, σ+, σI, σR) and F and R parameters

Frequency	Constants	r	I	ρ	s	n	Correlated derivatives
(E)-N benzylidene-4-morpholinoanilines
δ_CH=N	σ	0.781	8.485	0.053	0.11	11	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-CH₃, 4-NO₂
	σ⁺	0.854	8.490	0.043	0.11
	σ_I	0.749	8.510	–0.067	0.11
	σ_R	0.904	8.540	0.245	0.10	10	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 4-CH₃, 4-NO₂
	F	0.728	8.506	–0.054	0.11	11	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-CH₃, 4-NO₂
	R	0.903	8.543	0.181	0.10	10	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 4-CH₃, 4-NO₂
(E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines
δNH₂	σ	0.993	4.27	0.47	0.33	5	H, Br, Cl, OCH₃, CH₃
	σ⁺	0.995	4.29	0.18	0.33	5	H, Br, Cl, OCH₃, CH₃
	σ_I	0.905	4.06	0.74	0.28	5	H, Br, Cl, OCH₃, CH₃
	σ_R	0.905	4.05	-0.99	0.28	5	H, Br, Cl, OCH₃, CH₃
	F	0.907	4.00	0.86	0.21	5	H, Br, Cl, OCH₃, CH₃
	R	0.905	4.06	-0.72	0.29	5	H, Br, Cl, OCH₃, CH₃
δCH	σ	0.905	8.44	0.14	0.11	6	H, Br, Cl, F, CH₃
	σ⁺	0.981	8.34	0.37	0.04	6	H, Br, Cl, F, CH₃
	σ_I	0.907	8.36	-0.38	0.08	6	H, Br, Cl, F, CH₃
	σ_R	0.983	8.35	0.32	0.06	5	H, Br, Cl, F, CH₃
	F	0.906	8.36	-0.29	0.08	5	H, Br, Cl, F, CH₃
	R	0.908	8.25	0.45	0.09	5	H, Br, Cl, F, CH₃

r – Correlation coefficient; I – intercept; ρ – slope; s – standard deviation; n – number of substituents.

Since most of the single regression analysis have shown poor correlations with a few Hammett substituent constants and F parameter. It is decided to go for multi-regression analysis [49]. The multi-regression analysis of the chemical shifts (δ_CH=N, ppm) of substituted (E)-N benzylidene-4-morpholinoanilines with inductive, resonance and Swain-Lupton’s parameters[49] produce satisfactory correlations as shown in equations (9 and 10).

δ_CH=N (ppm) = 8.57(±0.065) – 0.096(±0.038)σ_I + 0.261(±0.068)σ_R

(R = 0.949, n = 11, P > 95%) … (9)

δ_CH=N (ppm) = 8.55(±0.058) – 0.049(±0.027)F + 0.180(±0.010)R

(R = 0.951, n = 11, P > 95%) … (10)

The NH proton NMR chemical shifts of (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines were tabulated in Table 3. the table 3, the Hammett sigma and sigma plus constants gave good correlations with NH chemical shifts with positive rho values excluding F substituent. The σ⁺, σ_I, constants, F and R parameters were shown satisfactory correlation coefficients excluding F substituents. If include the F, the correlation was significantly reduced. The electronegative character was not obeying the Hammett linear regression and deviate the reflecting the effect of substituent on NH chemical shifts. All single regressions except resonance components gave positive rho values. This implies that the normal substituents effect operates in all systems. The resonance components gave negative rho values and it revered the effect of substituents on NH chemical shifts. The reason for reversal substituent effect was the resonance and conjugative structures of the imines as shown in Fig. 3.

The Hammett sigma and sigma plus constants gave satisfactory and good correlations with CH = N chemical shifts with positive rho values excluding OCH₃ substituent. The σ_I constant F and R parameters were shown satisfactory correlation coefficients excluding OCH₃ substituent. The σ_R constant gave good correlations excluding OCH₃ substituent. If include the OCH₃ substituent, the correlation was significantly reduced. Except inductive and resonance components, remaining regression gave positive rho values. This implies that the normal substituents effect operates in all systems. The σ_I and R parameters gave negative rho values. The resonance components gave negative rho values and it reversed the effect of substituents on ¹H NMR CH = N CH = N chemical shifts. The reason for reversal substituent effect is the resonance and conjugative structures of the imines as shown in Fig. 3.

Aa few single correlations were failed for prediction of the substituent effects on the proton chemical shifts, then the authors studied the multi-regression analysis for finding the effect of substituents on the amino group chemical shifts (δ, ppm) using σ⁺, σ_R, F, R Swain-Lupton’s constants1[0, 18, 20, 22–27, 49]. The obtained the multilinear regression analysis shows a good correlation as in equations (11–14).

δNH₂ (ppm) = 4.00(± 0.21) + 0.46(± 0.67)σ_I − 0.60(± 0.90) σ_R …(11)

R = 0.966, P > 95%, n = 6

δNH₂ (ppm) = 3.99(± 0.17) + 0.85(± 0.53)F − 0.02(± 0.06)R …(12)

R = 0.978, P > 95%, n = 6

δCHN (ppm) = 8.32(± 0.03) + 0.31(± 0.01)σ_I − 0.12(± 0.43) σ_R …(13)

R = 0.993, P > 95%, n = 6

δCHN (ppm) = 8.34(± 0.05) + 0.25(± 0.15)F − 0.07(± 0.18)R …(14)

R = 0.987, P > 95%, n = 6

¹³ C NMR Correlations

The assigned ¹³C NMR chemical shifts (δ_C=N, ppm) of substituted (E)-N-benzylidene-4-morpholinoanilines are correlated with Hammett substituent constants and F and R parameters [10, 18, 20, 22–27, 49]. The results of statistical analysis are shown in Table 6.

Table 6

Results of statistical analysis of 13C NMR chemical shifts (δC = N, ppm) of (E)-N-benzylidene-4-morpholinoanilines and (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines with Hammett substituent constants (σ, σ⁺, σ_I, σ_R) and F and R parameters
Frequency	Constants	r	I	ρ	s	n	Correlated derivatives
(E)-N-benzylidene-4-morpholinoanilines
δ_C=N	σ	0.987	156.80	–2.575	0.78	8	3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 2-CH₃, 4-NO₂
	σ⁺	0.762	156.55	–1.046	1.07	11	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-CH₃, 4-NO₂
	σ_I	0.984	157.74	–4.143	0.69	10	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 4-CH₃, 4-NO₂
	σ_R	0.965	155.97	–2.731	1.15	9	3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-NO₂
	F	0.968	157.44	–3.149	0.94	9	H, 3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 3-OCH₃, 4-CH₃, 4-NO₂
	R	0.945	156.01	–1.794	1.16	9	3-Br, 4-Br, 3-Cl, 4-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃, 4-NO₂
(E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines
δ_C=N	σ	0.866	155.37	-0.67	0.21	6	H, Br, Cl, F, OCH₃, CH₃
	σ⁺	0.856	155.33	-0.32	0.21	6	H, Br, Cl, F, OCH₃, CH₃
	σ_I	0.851	155.44	-0.43	0.21	6	H, Br, Cl, F, OCH₃, CH₃
	σ_R	0.808	155.33	0.10	0.25	6	H, Br, Cl, F, OCH₃, CH₃
	F	0.853	155.50	-0.43	0.21	6	H, Br, Cl, F, OCH₃, CH₃
	R	0.806	155.38	0.62	0.25	6	H, Br, Cl, F, OCH₃, CH₃

From Table 6, it is observed that the ¹³C NMR chemical shifts (δ_C=N, ppm) of aryl (E)-imine compounds have shown satisfactory correlation with Hammett substituent constants (σ, σ_I, σ_R), F and R parameters except H, 3-OCH₃, 4-CH₃, 2-CH₃ and 4-F substituents. The remaining Hammett substituent constants σ⁺ were poor correlation. When the substituent that have been given exception are included in regression, they reduced the correlation considerably. All the correlation gave negative ρ values. This shows that the reverse substituent effect operates in all system. The reason for the poor correlation is the incapability of the substituent on the imine chemical shift and is associated with the resonance conjugative structure as shown in Fig. 2.

The correlation of carbon-13 chemical shifts of (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines were presented in table 5, the Hammett sigma and sigma plus constants, inductive, filed and resonance effects of substituents were failed in single linear regression correlations with CH = N chemical shifts (δ, ppm) with negative and positive rho values. The positive and negative rho values imply that the normal and reversal substituent effect operates in all system. Among these correlations, the sigma constant gave slightly better correlations. The failure in correlations are the resonance and conjugative structures of the imines as shown in Fig. 3.

Since a few of the single regression analysis have shown poor correlation with a few Hammett substituent constants and F and R parameters [49]. The multi-regression analysis of the chemical shifts (δ_C=N, ppm) of aryl (E)-imine compounds with inductive, resonance and Swain-Lupton’s parameters [49] produce satisfactory correlation as shown in equations (15–18.).

δ_C=N (ppm) = 157.26(±0.334) – 3.909(±0.705)σ_I – 2.073(±0.860)σ_R … (15) (R = 0.914, n = 11, P > 95%)

δ_C=N (ppm) = 156.91(±0.419) – 3.195(±0.919)F – 1.853(±0.793)R … (16) (R = 0.982, n = 11, P > 95%)

δ_C=N (ppm) = 155.45(± 0.17) − 0.66(± 5.33)σ_I − 0.42(± 0.71) σ_R … (17)

R = 0.958, P > 95%, n = 6

δ_C=N (ppm) = 155.44(± 0.15) − 0.73(± 0.47)F − 0.54(± 0.57)R … (18)

R = 0.966, P > 95%, n = 6

Assessment of Molecular Docking interactions

The docking enquiry of the ligands to protein active sites were carried out via Auto dock 4 for revealing the binding energies of the compounds. The designed compounds were docked towards the human estrogen receptor (2IOK). The compounds 1–28 showed good and better affinity to the receptor. The compound 19 and 21 has highest binding energy against breast cancer protein. The binding energy values of compounds 1–28 are listed out in the Table-7.

Table 7 Binding energy values of compounds 1-28

Entry	Ar	Ar′	Binding Energy ∆G (kcal/mol)
1	4-Morpholinoaniline	Phenyl	-5.69
2	4-Morpholinoaniline	3-Bromophenyl	-6.09
3	4-Morpholinoaniline	4-Bromophenyl	-5.25
4	4-Morpholinoaniline	3-Chlorophenyl	-5.81
5	4-Morpholinoaniline	4-Chlorophenyl	-5.98
6	4-Morpholinoaniline	4-Dimethylaminophenyl	-5.37
7	4-Morpholinoaniline	4-Florophenyl	-5.72
8	4-Morpholinoaniline	3-Methoxyphenyl	-5.23
9	4-Morpholinoaniline	2-Methylphenyl	-6.10
10	4-Morpholinoaniline	4-Methylphenyl	-5.67
11	4-Morpholinoaniline	4-Nitrophenyl	-5.28
12	Phenyl	2-Amino-4,6-dibromophenyl	-6.04
13	4-Bromophenyl	2-Amino-4,6-dibromophenyl	-6.07
14	4-Chlorophenyl	2-Amino-4,6-dibromophenyl	-6.4
15	4-Florophenyl	2-Amino-4,6-dibromophenyl	-5.80
16	4-Methoxyphenyl	2-Amino-4,6-dibromophenyl	-5.67
17	4-Methylphenyl	2-Amino-4,6-dibromophenyl	-6.36
18	1-Benzyl-4-piperidinyl	Phenyl	-6.28
19	1-Benzyl-4-piperidinyl	3-Bromophenyl	-6.81
20	1-Benzyl-4-piperidinyl	3-Chlorophenyl	-6.24
21	1-Benzyl-4-piperidinyl	4-Chlorophenyl	-6.99
22	1-Benzyl-4-piperidinyl	4-Dimethylaminophenyl	-6.36
23	1-Benzyl-4-piperidinyl	4-Fluorophenyl	-6.49
24	1-Benzyl-4-piperidinyl	3-Methoxyphenyl	-6.01
25	1-Benzyl-4-piperidinyl	4-Methoxyphenyl	-6.45
26	1-Benzyl-4-piperidinyl	4-Methylphenyl	-6.69
27	1-Benzyl-4-piperidinyl	3-Nitrophenyl	-6.04
28	1-Benzyl-4-piperidinyl	4-Nitrophenyl	-6.00

The docking results of 4-morpholino aniline based Imines (1–11) these designed ligands docked with human estrogen receptor 2IOK and revealed the binding energy values ranging from (-5.23 to -kcal/mol) The highest active compounds 2 and 9 consists of binding energy values − 6.09 and − 6.1 respectively. The compound 2 have Amino acid residues are GLU B: 1443 (Glutamic acid, Electrostatic bond interaction), GLY B:1442, LEU B:1320, PHE B:1445 and PRO B:1324 (Glycine, Leucine, Phenylalanine and Proline) and these are hydrophobic bond interactions. The compound 9 have amino acid residues are GLU A:323(Glutamic acid, Electrostatic bond interaction), ILE A:326, LEU A:327, PRO A:324,, TRP A:393 and VAL A:446 (Isoleucine, Leucine, Proline, Glutamic acid, Tryptophan and Valine), these are hydrophobic bond interactions. These docking result shown might be due to the presence of halogen group substitutions. The 2D and 3D image of highest binding energies of compounds 2 and 9 shown in Table-8.

The docking results of 2-Amino-4,6-dibromophenyl based imines (12–17) this designed ligands docked with human estrogen receptor 2IOK and revealed the binding energy values ranging from (-5.67 to -6.4kcal/mol) The highest active compounds 14 and 17 consists of binding energy values − 6.4 and − 6.36 respectively. The compound 14 have Amino acid residues are GLU A: 423 (Glutamic acid, Electrostatic bond interaction), ARG A:412, ASP A:426 (Arginine and Aspartic acid, Electrostatic bond interactions), ALA A:430, LEU B:1462 (Alanine and Leucine, Hydrophobic bond interactions), TYRB:1459, SER B:1464 (Tyrosine and Serine, Hydrogen bond interactions). The compound 17 have amino acid residues are ARG B:1394, GLU B:1323(Arginine and Glutamic acid, Electrostatic bond interaction), ILE B:1326, LEU B:1320, LEU B:1327, (Isoleucine and Leucine, hydrophobic bond interactions), These docking results shown might be due to the presence of halogen group substitutions. The 2D and 3D image of highest binding energies of compounds 14 and 17 shown in Table-8.

The docking results of 1-benzyl-4-piperidinyl based imines (18–28), these designed ligands docked with human estrogen receptor 2IOK and revealed the binding energy values ranging from (-6.0 to -6.99kcal/mol) The highest active compounds 19, 21 and 26 consists of binding energy values − 6.99, -6.81 and − 6.69 respectively. The compound 19 have Amino acid residues are CYS A:417, LEU A:408, LEU A:409, MET A:342(Cysteine, Leucine, Methionine, Hydrophobic bond interactions), GLN A:414 and SER A:341 (Glutamine and Serine, Hydrogen bond interactions). The compound 21 have amino acid residues are ASP B:1351 (Aspartic acid, Electrostatic bond interactions), ALA B:1350, LEU B:1525, LEU B:1539, MET B:1543 and VAL B:1355 (Alanine, Leucine, Methionine and Valine, Hydrophobic bond interactions). The compound 26 have amino acid residues are ALA A:350, LEU A:354, LEU A:536, LEU A:539, PRO A:535, TRP A:383 (Alanine, Leucine, Proline and Tryptophan, Hydrophobic bond interactions). These docking results shown might be due to the presence of halogen group substitutions. The 2D and 3D image of highest binding energies of compounds 19, 21 and 26 shown in Table-8.

Antibacterial activity assessment

The antibacterial effect of the substituted (E)-N-benzylidene- 4-morpholinoanilines is shown in Fig. 4 and the zone of inhibition values [18, 23, 24, 25, 27, 50–61] are given Table 9. The corresponding clustered column chart is given in Fig. 4. The aryl (E)-imine compounds with H, 4-Br, 3-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃ and 2-CH₃ substituents have shown good antibacterial activity and the remaining substituted aryl (E)-imine compounds are not active against B. subtilis bacterial strain. The aryl (E)-imine compounds with 4-CH₃ and 2-CH₃ substituents have shown good antibacterial activity and all the remaining substituted aryl (E)-imine compounds have shown moderate activity against M. luteus bacterial strain. The aryl (E)-imine compounds with 3-Cl and 4-Cl substituents have shown good antibacterial activity. The compounds with H, 3-Br, 4-Br, 4-N(CH₃)₂, 4-F, 3-OCH₃, 2-CH₃ and 4-NO₂ substituents have shown moderate antibacterial activities and the remaining compounds are not active against S. aureus bacterial strain. The aryl (E)-imine compounds with H, 3-Br, 4-Br, 3-Cl, 2-CH₃ and 4-NO₂ substituents have shown moderate antibacterial activity and the remaining compounds are not active against E. coli bacterial strain. All the substituted aryl (E)-imine compounds have shown moderate antibacterial activity except 4-N(CH₃)₂ and 3-Cl against P. aeruginosa and K. pneumoniae.

Table 9

Antibacterial activities of substituted (E)-N-benzylidene- 4-morpholinoanilines
Entry	Substituent	Zone of inhibition (mm)
		Gram-positive			Gram-negative
		B. subtilis	M. luteus	S. aureus	E. coli	P. aeruginosa	K. pneumoniae
1	H	6	6	6	6	7	6
2	3-Br	–	6	7	6	7	8
3	4-Br	6	6	7	6	7	6
4	3-Cl	6	6	8	6	8	–
5	4-Cl	–	6	8	–	6	5
6	4-N(CH₃)₂	6	6	7	–	–	6
7	4-F	6	6	6	–	6	7
8	3-OCH₃	6	6	6	–	6	6
9	2-CH₃	6	7	7	6	7	7
10	4-CH₃	–	8	–	–	6	6
11	4-NO₂	–	6	6	6	6	7
Ampicillin		9	7	12	10	12	12

Antifungal activity assessment

The antifungal activities by means of mm of zone of inhibition [18, 23, 24, 25, 27, 50–61] of substituted (E)-N-benzylidene-4-morpholinoaniline compounds in (E)-N-benzylidene- 4-morpholinoanilines shown in Fig. 6 and the zone of inhibition values are given in Table 10. The corresponding clustered column chart is shown in Fig. 7.

Table 11. Antifungal activities of (E)-N-benzylidene- 4-morpholinoanilines

Entry	Substituent	Zone of inhibition (mm)
Entry	Substituent	A. niger	Mucor sp.	T. viride
1	H	–	–	–
2	3-Br	–	–	–
3	4-Br	6	–	6
4	3-Cl	–	6	6
5	4-Cl	6	6	6
6	4-N(CH₃)₂	6	–	–
7	4-F	–	–	–
8	3-OCH₃	6	6	–
9	2-CH₃	–	7	–
10	4-CH₃	–	–	–
11	4-NO₂	6	–	–
Miconazole		11	10	11

The aryl (E)-imine compounds with 4-Br, 4-Cl, 4-N(CH₃)₂, 3-OCH₃, 4-NO₂ substituents have shown moderate activity and the remaining compounds have no activity against A. niger fungal strain. The analysis of aryl (E)-imine compounds with 3-Cl, 4-Cl, 3-OCH₃ and 2-CH₃ substituents have shown moderate antifungal activity. The remaining compounds are not active against Mucor species fungal strain. The aryl (E)-imine compounds with 4-Br, 3-Cl and 4-Cl substituents have shown moderate antifungal activity. The remaining compounds have no activity against T. viride fungal strain.

Antimalarial activity assessment

The measured in-vitro antimalarial activities of the synthesized E-imines are presented in Table 11. From the Table 11, All halogen substituted imines shows good antimalarial activities against the falciparum stain. Among these halogenated imines 14 and 13 shows signifying antimalarial activity. Then compounds 12, 15–17 shows somewhat less antimalarial activity comparatively imine 13 and 14. Here the inductive effects of halogens enhance the antimalarial activity. The imines 2–5, 7, 19–21 and 23 shows moderate antimalarial activity. The imines 1. 6, 8–11, 18 and 24–28 shows lesser antimalarial activity. Here the + I effect of Phenyl, Dimethylamine, methyl, nitro, groups considerably reduce the antimalarial activity. Even the -I effect of methoxy group also surprisingly reduces the antimalarial activity associated with the resonance conjugative structures 2 and 6.

Table 11

Antimalarial activities of synthesised imines of the synthesized imines

Entry	Ar	Ar′	Antimalarial Inhibition (%)
1	4-Morpholinoaniline	Phenyl	23 ± 0.46
2	4-Morpholinoaniline	3-Bromophenyl	32 ± 0.16
3	4-Morpholinoaniline	4-Bromophenyl	32 ± 0.21
4	4-Morpholinoaniline	3-Chlorophenyl	32 ± 0.11
5	4-Morpholinoaniline	4-Chlorophenyl	32 ± 0.13
6	4-Morpholinoaniline	4-Dimethylaminophenyl	17 ± 0.16
7	4-Morpholinoaniline	4-Florophenyl	31 ± 0.26
8	4-Morpholinoaniline	3-Methoxyphenyl	20 ± 0.17
9	4-Morpholinoaniline	2-Methylphenyl	26 ± 0.13
10	4-Morpholinoaniline	4-Methylphenyl	25 ± 0.11
11	4-Morpholinoaniline	4-Nitrophenyl	24 ± 0.66
12	Phenyl	2-Amino-4,6-dibromophenyl	32 ± 0.26
13	4-Bromophenyl	2-Amino-4,6-dibromophenyl	34 ± 0.02
14	4-Chlorophenyl	2-Amino-4,6-dibromophenyl	34 ± 0.06
15	4-Florophenyl	2-Amino-4,6-dibromophenyl	33 ± 0.43
16	4-Methoxyphenyl	2-Amino-4,6-dibromophenyl	33 ± 0.12
17	4-Methylphenyl	2-Amino-4,6-dibromophenyl	33 ± 0.43
18	1-Benzyl-4-piperidinyl	Phenyl	22 ± 0.06
19	1-Benzyl-4-piperidinyl	3-Bromophenyl	31 ± 0.36
20	1-Benzyl-4-piperidinyl	3-Chlorophenyl	32 ± 0.32
21	1-Benzyl-4-piperidinyl	4-Chlorophenyl	32 ± 0.76
22	1-Benzyl-4-piperidinyl	4-Dimethylaminophenyl	28 ± 0.91
23	1-Benzyl-4-piperidinyl	4-Fluorophenyl	31 ± 0.46
24	1-Benzyl-4-piperidinyl	3-Methoxyphenyl	25 ± 0.21
25	1-Benzyl-4-piperidinyl	4-Methoxyphenyl	23 ± 0.88
26	1-Benzyl-4-piperidinyl	4-Methylphenyl	25 ± 0.54
27	1-Benzyl-4-piperidinyl	3-Nitrophenyl	18 ± 0.73
28	1-Benzyl-4-piperidinyl	4-Nitrophenyl	20 ± 0.92

There are twenty-eight E-imines were synthesized using greener synthetic method. In this synthesis, the nano fly-ash: H₃PO₄ catalyst was used for the condensation of various aryl anilines and benzaldehydes under ultrasonication conditions in greener solvent medium. This methodology followed the green chemistry criteria such as high yield, lesser time and pollution free solvent usages. The synthesized Schiff’s bases were analyzed with their physico-chemical parameters, micro analysis and spectrometry. The characteristic spectral frequencies were utilized for the study of QSAR with Hammett σ, σ, σ_I, σ_R F R and Swain-Lupton’s constants. In IR spectral correlations, the σ, σ⁺ and resonance parameters were produced satisfactory correlations with CN stretches of amines. All Hammett parameters shows satisfactory correlations with NH₂ vibrations. Some of the correlations produced -ρ values. In ¹H NMR spectral correlations, the resonance component only gave satisfactory correlation with CH chemical shifts of (E)-N benzylidene-4-morpholinoanilines. The CH and NH chemical shifts of (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines were correlated satisfactorily with Hammett substituent constants, F and R parameters. The correlation of carbon-13 chemical shifts(ppm) of CN group (E)-N-benzylidene-4-morpholinoanilines was satisfactorily correlated except σ⁺ constant. The same analysis was failed in (E)-3,5-Dibromo-2-((4-substituted phenyl imino) methyl) anilines. All multi-regression analysis of the imines produced satisfactory correlation coefficients. The molecular docking study shows the imines 2, 9, 14, 17, 19, 21 and 26 produced the good binding interaction energies with respected proteins. The aryl (E)-imine compounds (1–11) with H, 4-Br, 3-Cl, 4-N(CH₃)₂, 4-F, 3-OCH₃ and 2-CH₃ substituents have shown good antibacterial activity against their antibacterial stains. The aryl (E)-imine compounds (1–11) with 4-Br, 4-Cl, 4-N(CH₃)₂, 3-OCH₃, 4-NO₂ substituents have shown moderate activity against their fungal stains. The halogenated imines 14 and 13 shows signifying antimalarial activity. Then compounds 12, 15–17 shows somewhat less antimalarial activity comparatively imine 13 and 14.

Supplementary Information

NMR spectra, LCMS spectra with their mass fragments, preparation and characterization of nano fly-ash: H₃PO₄ catalyst available.

Acknowledgements

Authors thank to DST-FIST NMR facility, Department of Chemistry, Annamalai University, Annamalainagar-608002, India for recording NMR spectra of compounds.

Authors’ contributions

P. Mayavel contributed to conceptualization, formal analysis, investigation validation, visualization, J. Divya contributed to formal analysis, investigation validation, visualization and writing, P. Gayathri contributed to conceptualization, formal analysis, investigation validation, visualization, S. Balasundari contributed to conceptualization, formal analysis, investigation validation, visualization, V. Usha contributed to conceptualization, formal analysis, investigation validation, visualization, I. Muthuvelcontributed to conceptualization, formal analysis, investigation validation, visualization, G. Thirunarayanan contributed to conceptualization project administration, funding acquisition, writing—original draft, and writing—review and editing.

Funding

This work was supported and completed from the RUSA-2, Field 1, Anti-Malarial Drug Synthesis, Project, No. F3/RUSA/673/2022 dated 4-6-2022, Annamalai University, Annamalainagar-608 002, India.

Conflict of interest: The authors declare that they have no competing interests.

Ethical approval: Not applicable.

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Table 8 is available in the Supplementary Files section.

Schemes 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

ROCIPMImineSuppdata.docx
Table8.docx
scheme1.png
Scheme 1. Synthesis of E-imines by nano fly-ash: H₃PO₄ catalyzed ultrasonicated condensation of aryl amine and aldehydes.
scheme2.png
Scheme 2. The mechanistic path way of synthesis of E-imines by nano fly-ash: H₃PO₄ catalyzed condensation of amine and aldehydes under ultrasonication irradiation.

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Ultrasound assisted synthesis and spectral correlations of some bio-active E-imines

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Experimental

Materials and Methods

Molecular docking analysis

Measurement of Antibacterial activity

Measurement of Antifungal activity

Measurement of Antimalarial activity

Results and discussion

Chemistry

Spectral correlations

Inferred spectral correlations

ν = ρσ + ν₀ …(1)

NMR spectral correlations

δ = ρσ + δ₀ … (8)

Assessment of Molecular Docking interactions

Antibacterial activity assessment

Antifungal activity assessment

Antimalarial activity assessment

Conclusions

Declarations

References

Table 8

Schemes

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1

Ultrasound assisted synthesis and spectral correlations of some bio-active E-imines

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Experimental

Materials and Methods

Molecular docking analysis

Measurement of Antibacterial activity

Measurement of Antifungal activity

Measurement of Antimalarial activity

Results and discussion

Chemistry

Spectral correlations

Inferred spectral correlations

ν = ρσ + ν0 …(1)

NMR spectral correlations

δ = ρσ + δ0 … (8)

Assessment of Molecular Docking interactions

Antibacterial activity assessment

Antifungal activity assessment

Antimalarial activity assessment

Conclusions

Declarations

References

Table 8

Schemes

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1

ν = ρσ + ν₀ …(1)

δ = ρσ + δ₀ … (8)